title: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer.
  
  
  METHODS
  We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384.
  
  
  RESULTS
  355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug.
  
  
  CONCLUSIONS
  Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer.
  
  
  BACKGROUND
  ImClone Systems.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address: cfuchs@partners.org.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Department of Complex Oncology Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Tomasek
authors.affiliation: Department of Medical Oncology, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea.
authors.forename: Cho Jae
authors.initials: CJ
authors.lastname: Yong
authors.affiliation: Oncology Department, Emergency County Hospital "Dr Constantin Opris", Baia Mare, Romania.
authors.forename: Filip
authors.initials: F
authors.lastname: Dumitru
authors.affiliation: Medical Oncology Division, Istituti Ospitalieri di Cremona, Cremona, Italy.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Passalacqua
authors.affiliation: Department of Medical Oncology, B P Poddar Hospital and Medical Research, Kolkata, West Bengal.
authors.forename: Chanchal
authors.initials: C
authors.lastname: Goswami
authors.affiliation: Department of Medicine, The Brown University Oncology Group, Brown University, Providence, RI, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Safran
authors.affiliation: Medical Oncology Department, Gastrointestinal Oncology Division, Hospital de Câncer de Barretos and Hemomed Instituto de Oncologia e Hematologia, São Paulo, Brazil.
authors.forename: Lucas Vieira
authors.initials: LV
authors.lastname: Dos Santos
authors.affiliation: Department of Oncology, University and General Hospital, Udine, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Aprile
authors.affiliation: Department of Medical Oncology, New Cross Hospital, West Midlands, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Ferry
authors.affiliation: Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, CzechRepublic.
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Melichar
authors.affiliation: Department of Medical Oncology, Hôpital Notre Dame de CHUM, Montreal, Quebec.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Tehfe
authors.affiliation: State Budgetary Educational Institution of Higher Professional Education (SBEIHPE), "Northwest State Medical University na II Mechnikov", Ministry of Healthcare of the Russian Federation, Russia.
authors.forename: Eldar
authors.initials: E
authors.lastname: Topuzov
authors.affiliation: Division of Cancer Medicine, Peter McCallum Cancer Centre, East Melbourne, VIC, Australia; Departments of Medicine and Oncology, Faculty of Medicine, University of Melbourne, Australia.
authors.forename: John Raymond
authors.initials: JR
authors.lastname: Zalcberg
authors.affiliation: Department of Medicine, Royal Marsden Hospital, London and Surrey, England.
authors.forename: Ian
authors.initials: I
authors.lastname: Chau
authors.affiliation: Department of Oncology, Hospital Herrera Llerandi-Clinicas Médicas, Guatemala.
authors.forename: William
authors.initials: W
authors.lastname: Campbell
authors.affiliation: Division of Cancer Research, Regional Cancer Centre, Kerala, India.
authors.forename: Choondal
authors.initials: C
authors.lastname: Sivanandan
authors.affiliation: Wojewódzkie Centrum Onkologii Gdańsk, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Pikiel
authors.affiliation: ImClone Systems LLC, Bridgewater, NJ, USA.
authors.forename: Minori
authors.initials: M
authors.lastname: Koshiji
authors.affiliation: ImClone Systems LLC, Bridgewater, NJ, USA.
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Hsu
authors.affiliation: Eli Lilly, Indianapolis, IN, USA.
authors.forename: Astra M
authors.initials: AM
authors.lastname: Liepa
authors.affiliation: ImClone Systems LLC, Bridgewater, NJ, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: ImClone Systems LLC, Bridgewater, NJ, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schwartz
authors.affiliation: Medical Oncology Department Vall d'Hebron University Hospital, UniversitatAutònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018450:Disease Progression; D004311:Double-Blind Method; D004938:Esophageal Neoplasms / Q000188:drug therapy; D004943:Esophagogastric Junction; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D013274:Stomach Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D055815:Young Adult; D000096662:Ramucirumab
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D040301:Vascular Endothelial Growth Factor Receptor-2; D000096662:Ramucirumab